PROJECT SUMMARY/ABSTRACT Worldwide, adenocarcinoma of the stomach is the third leading cause of cancer-related mortality, and H. pylori infection is the most common predisposing factor for the development of gastric cancer. H. pylori is typically acquired in early childhood, but children with H. pylori infection rarely develop precancerous lesions and primary gastric cancer is all but non-existent compared with >700 cases per 100,000 adults. These findings suggest that the gastric mucosa of children contains protective mechanisms that suppress H. pylori-associated precancerous inflammation and the development of gastric adenocarcinoma compared with the gastric mucosa of adults. Understanding the early events in the childhood mucosal response to H. pylori infection is critical for devising immune-based strategies to prevent or limit the precancerous inflammation. In dissecting these early events in subjects in Chile, where the infection and gastric adenocarcinoma are endemic, we have discovered that H. pylori-infected children have significantly increased gastric regulatory T (Treg) cell responses with reciprocally reduced Th1/Th17-mediated gastric inflammation compared with infected adults, despite similar H. pylori colonization levels, virulence and genotype. These findings suggest that other factors likely drive to the enhanced Treg responses that suppress gastric inflammation in children. Since certain colonic microbiota have been shown to induce mucosal Tregs to suppress experimental colitis in mice, we hypothesize that the gastric microbiota in children induces H. pylori to drive gastric mucosal Treg responses that suppress the Th1 and Th17 gastric inflammation, which in adults predisposes to gastric cancer. Addressing this hypothesis, we have identified distinct differences in the microbiota in the stomachs of H. pylori-infected children compared with that of infected adults. Therefore, we propose to determine whether H. pylori plus the gastric microbiota from children, in contrast to the microbiota from infected adults, stimulate epithelial cells derived from stem cell organogenesis to induce gastric (mucosalized) dendritic cells that promote enhanced Treg suppression of cancer-predisposing mucosal inflammation.